The regulatory landscape of macrophage interferon signaling in inflammation
Authors: Ricky Siebeler, Menno P.J. de Winther, Marten A. Hoeksema
Journal: Journal of Allergy and Clinical Immunology (2023)

The pervasive role of the innate immune system is established by interferons. Emerging research shows an underappreciated ability of macrophages to regulate and propagate interferon responses in infectious and autoinflammatory disease states. In this review, we will discuss recent findings demonstrating the immunomodulating effects of macrophage interferon signaling. Apart from provoking cellular antimicrobial defenses, interferons augment the inflammatory activity of macrophages. These immunologic adaptations place the macrophage in the center of the interferon system and at the forefront of immunity. Consequently, macrophages are implicated in the pathogenesis of interferon-driven autoinflammatory disorders, such as SLE. In these disease states, the recognition of immunogenic ligands triggers macrophages to adopt an inflammatory phenotype through interferon signaling. This will amplify immune responses, eventually leading to autoinflammation. A better understanding of the macrophage's role in interferon signaling will support the future elucidation of novel targets amendable for clinical treatment. The pervasive role of the innate immune system is established by interferons. Emerging research shows an underappreciated ability of macrophages to regulate and propagate interferon responses in infectious and autoinflammatory disease states. In this review, we will discuss recent findings demonstrating the immunomodulating effects of macrophage interferon signaling. Apart from provoking cellular antimicrobial defenses, interferons augment the inflammatory activity of macrophages. These immunologic adaptations place the macrophage in the center of the interferon system and at the forefront of immunity. Consequently, macrophages are implicated in the pathogenesis of interferon-driven autoinflammatory disorders, such as SLE. In these disease states, the recognition of immunogenic ligands triggers macrophages to adopt an inflammatory phenotype through interferon signaling. This will amplify immune responses, eventually leading to autoinflammation. A better understanding of the macrophage's role in interferon signaling will support the future elucidation of novel targets amendable for clinical treatment. Interferons (IFNs) underlie the competence of the innate immune system to ward off pathogens. In viral infections, IFNs are secreted to induce an antiviral state in host cells, supporting our first line of defense against pathogens.1Durbin J.E. Fernandez-Sesma A. Lee C.K. Rao T.D. Frey A.B. Moran T.M. et al.Type I IFN modulates innate and specific antiviral immunity.J Immunol. 2000; 164: 4220-4228Crossref PubMed Google Scholar Moreover, IFNs recruit leukocytes to the site of infection and augment their activity.2Lee A.J. Ashkar A.A. The dual nature of type I and type II interferons.Front Immunol. 2018; 9: 2061Crossref PubMed Scopus (343) Google Scholar These measures ultimately aim to interfere with viral replication and dissemination, curtailing the infection. Perturbed IFN responses may therefore underlie severity and susceptibility to viral infections.3Posseme C. Llibre A. Charbit B. Bondet V. Rouilly V. Saint-André V. et al.Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation.Cell Rep. 2022; 39110989Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Predictably, impaired IFN responses are a hallmark of severe COVID-19 manifestation.4Stertz S. Hale B.G. Interferon system deficiencies exacerbating severe pandemic virus infections.Trends Microbiol. 2021; 29: 973-982Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,5Hadjadj J. Yatim N. Barnabei L. Corneau A. Boussier J. Smith N. et al.Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.Science (1979). 2020; 369: 718-724Crossref PubMed Scopus (0) Google Scholar More than half a century of research since their discovery, the role of IFNs is now known to extend well beyond antiviral responses. Namely, IFNs orchestrate various distinct homeostatic processes and immune responses to maintain physiological integrity.6Place D.E. Malireddi R.K.S. Kim J. Vogel P. Yamamoto M. Kanneganti T.D. Osteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins.Nat Commun. 2021; 12: 1-9Crossref PubMed Scopus (35) Google Scholar,7Katlinskaya Y.V. Katlinski K.V. Lasri A. Li N. Beiting D.P. Durham A.C. et al.Type I interferons control proliferation and function of the intestinal epithelium.Mol Cell Biol. 2016; 36: 1124-1135Crossref PubMed Scopus (26) Google Scholar Accordingly, disconcerted IFN responses have long been implicated to drive various autoinflammatory disorders, such as SLE and Aicardi-Goutières syndrome. In addition, IFNs commonly contribute to local or systemic inflammation as seen in rheumatoid arthritis and macrophage activation syndrome. Because perturbed IFN signaling appears as a common denominator in these conditions, they are now widely recognized as so-called interferonopathies. The pervasive role of IFNs necessitates investigative efforts into all facets of the IFN system to infer clinically relevant targets to reduce the burden of inflammatory disease. The IFN system is directed toward interfering with microbial dissemination, principally by enhancing interferon-stimulated gene (ISG) expression. On infection, nearly any host cell will produce IFNs as an intrinsic response against microbials, but also to protect neighboring cells and activate leukocytes. Purposely, some leukocytes are competent producers of IFNs themselves and highly responsive to the regulatory effects of IFNs, forming a feed-forward loop. The capacity of leukocytes to produce IFNs is dependent on cell lineage and cellular microenvironment, like the presence of pathogens and cytokines. Classically, there are lineages of cells specialized in the secretion of specific types of IFNs. For instance, plasmacytoid dendritic cells are accepted to be the predominant producers of type I and type III IFNs, whereas T cells are the foremost type II IFN-secreting leukocytes.8Fitzgerald-Bocarsly P. Dai J. Singh S. Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history.Cytokine Growth Factor Rev. 2008; 19: 3Crossref PubMed Scopus (261) Google Scholar, 9Psarras A. Alase A. Antanaviciute A. Carr I.M. 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The dual nature of macrophages, being both tissue-resident and derived from migratory monocytes, facilitates their universal role in tissue homeostasis and immunity.16Zhang C. Yang M. Ericsson A.C. Function of macrophages in disease: current understanding on molecular mechanisms.Front Immunol. 2021; 12: 635Google Scholar Importantly, macrophages are effective mediators of immunity by taking on the role of judge, jury, and executioner in innate immune responses. Pathogen recognition receptors (PRRs) constitute a wide number of sensors macrophages use to judge environmental exposures, such as pathogen-associated molecular patterns (PAMPs). The main PRRs to consider for IFN responses are transmembrane receptors such as Toll-like receptors (TLRs) and cytosolic receptors such as retinoic acid–inducible gene 1 (RIG-I) and melanoma differentiation–associated gene 5 (MDA5). Macrophages use their repertoire of PRRs and mediators to discriminate between intracellular versus extracellular pathogens, viral versus bacterial, and endogenous versus exogenous exposures, effectively enabling macrophages to execute an appropriate set of actions in response to their environment, including the propagation of an IFN response. Apart from secreting IFNs, macrophages are responsive to IFNs, placing them in the center of the IFN system.1Durbin J.E. Fernandez-Sesma A. Lee C.K. Rao T.D. Frey A.B. Moran T.M. et al.Type I IFN modulates innate and specific antiviral immunity.J Immunol. 2000; 164: 4220-4228Crossref PubMed Google Scholar,12Ali S. Mann-Nüttel R. Schulze A. Richter L. Alferink J. Scheu S. Sources of type I interferons in infectious immunity: plasmacytoid dendritic cells not always in the driver's seat.Front Immunol. 2019; 10: 778Crossref PubMed Scopus (33) Google Scholar Yet, this central role also implicates macrophages in interferonopathies.17Chen H.J. Tas S.W. de Winther M.P.J. Type-I interferons in atherosclerosis.J Exp Med. 2020; 217e20190459Crossref Scopus (39) Google Scholar,18Moulton V.R. Suarez-Fueyo A. Meidan E. Li H. Mizui M. Tsokos G.C. Pathogenesis of human systemic lupus erythematosus: a cellular perspective.Trends Mol Med. 2017; 23: 615Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar Transcriptional profiling using state-of-the-art technological advancements has allowed for the characterization of processes steering the IFN system, shedding light on delicate regulatory cascades. This review will cover the current understanding of regulatory networks underlying IFN responses in macrophages. An integral feature of IFNs is their ability to enhance cellular responsiveness to immunologic challenges. These effects were first observed more than 50 years ago and are yet to be fully elucidated.19Stewart II, W.E. Gosser L.B. Lockart Jr., R.Z. Priming: a nonantiviral function of interferon.J Virol. 1971; 7: 792Crossref PubMed Google Scholar Since then, the IFN system is established to comprise 3 classes of cytokines: type I, II, and III IFNs. There are several subclasses of type I (including IFN-α subtypes and IFN-β) and III IFNs (IFN-λ1 to 4), and a single type II IFN (IFN-γ). The evolutionary advantage of these subclasses is largely unknown, but functional differences come down to receptor affinity.20Wittling M.C. Cahalan S.R. Levenson E.A. Rabin R.L. Shared and unique features of human interferon-beta and interferon-alpha subtypes.Front Immunol. 2021; 11: 3325Crossref Scopus (22) Google Scholar,21Jaks E. Gavutis M. Uzé G. Martal J. Piehler J. Differential receptor subunit affinities of type I interferons govern differential signal activation.J Mol Biol. 2007; 366: 525-539Crossref PubMed Scopus (166) Google Scholar Despite shared nomenclature, the different types of IFNs share little structural homology.22Ealick S.E. 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Biochemically, the binding of type I IFNs to IFN-α/β receptor 1 and 2 triggers conformational change, allowing tyrosine kinase 2 and Janus kinase (JAK) 1 to phosphorylate signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2), causing heterodimerization. STAT1/STAT2 recruits IFN regulatory factor 9 (IRF9) to assemble heterotrimeric transcription complex IFN-stimulated gene factor 3 (ISGF3). Distinctly, type II IFN binds IFN-γ receptor 1 and 2, leading to JAK1- and JAK2-mediated phosphorylation and homodimerization of STAT1. The newly formed transcription complex IFN-γ activation factor will canonically translocate to the nucleus to bind gamma-activated sequence promoter elements, whereas ISGF3 binds IFN-stimulated response elements (ISREs), both promoting the expression of ISGs. Type III IFNs bind a heterodimeric receptor of IFN-λ receptor 1 and IL-10 receptor beta subunit, yet share their downstream signaling pathway with type I IFNs (Fig 1). ISGs are located downstream of ISREs, mainly encoding proteins with antimicrobial properties to protect the host from pathogenic exposures. Some of the most well-characterized ISGs are oligoadenylate synthetases, IFN-induced proteins with tetratricopeptide repeats, and IFN-induced GTP-binding protein. Strikingly, IRFs are also ISGs, thus generating a positive feedback loop in the transcription of ISGs. Similarly, various PRRs are under the control of ISREs. Altogether ISGs work in concert, targeting all stages of the viral life-cycle, from entry to egress.25Schoggins J.W. Interferon-stimulated genes: what do they all do?.Annu Rev Virol. 2019; 6: 567-584Crossref PubMed Scopus (380) Google Scholar ISGs are extensively studied in viral infections, but given how studying IFNs in nonviral immunity is relatively novel, little is known about the antibacterial properties of ISGs. 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Minute quantities of type I IFN, below the detection threshold of common assays, can have a significant influence on IFN signatures.49Willemsen L. Chen H.J. Roomen CPAA van Griffith G.R. Siebeler R. Neele A.E. et al.Monocyte and macrophage lipid accumulation results in down-regulated type-I interferon responses.Front Cardiovasc Med. 2022; 9829877Crossref PubMed Scopus (4) Google Scholar This phenomenon is well illustrated by IFN signaling under homeostatic conditions, which is facilitated by low-level type I IFN secretion. One of the main roles of IFNs, in absence of environmental challenges, is to prime immune cells.50Gough D.J. Messina N.L. Clarke C.J.P. Johnstone R.W. Levy D.E. Constitutive type I interferon modulates homeostatic balance through tonic signaling.Immunity. 2012; 36: 166Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar For instance, macrophages show microbiota-driven priming by IFN, offering protection against subsequent viral infection.51Abt M.C. 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ISRE-reporter mouse reveals high basal and induced type I IFN responses in inflammatory monocytes.Cell Rep. 2018; 25: 2784Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Basal IFN signaling was most strongly observed in monocytes, and this priming effect was shown to be critical to their antiviral responsiveness in vivo. Besides immunologic responses, myeloid-lineage cells mediate tissue homeostasis. The IFN pathway is pivotal to osteoclast differentiation and homeostasis, where IFNs mainly serve as negative feedback signals to the expression of transcription factors involved in osteoclastogenesis.6Place D.E. Malireddi R.K.S. Kim J. Vogel P. Yamamoto M. Kanneganti T.D. 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Manioudaki M. et al.Interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness.Immunity. 2017; 46: 875-890.e6Abs